EP0110755B1 - Piperidindion-Derivate mit herzmuskelschonender und antiarrhythmischer Wirkung, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel - Google Patents

Piperidindion-Derivate mit herzmuskelschonender und antiarrhythmischer Wirkung, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel Download PDF

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Publication number
EP0110755B1
EP0110755B1 EP83402142A EP83402142A EP0110755B1 EP 0110755 B1 EP0110755 B1 EP 0110755B1 EP 83402142 A EP83402142 A EP 83402142A EP 83402142 A EP83402142 A EP 83402142A EP 0110755 B1 EP0110755 B1 EP 0110755B1
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Prior art keywords
formula
group
product
piperidinedione
derivatives
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French (fr)
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EP0110755A1 (de
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Claude Bernhart
Werner Cautreels
Patrick Gautier
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Sanofi SA
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Sanofi SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles

Definitions

  • the present invention relates, as new industrial products, to derivatives of piperidinedione-2,6, as well as to their methods of preparation and their therapeutic application.
  • Said derivatives are substituted in position 3 with a pyridyl group and can in particular be used as protectors of the myocardium.
  • the compounds (I) provide with the organic or mineral acids soluble salts. These salts with pharmaceutically acceptable acids form an integral part of the invention.
  • the compounds (I) always have an asymmetric carbon atom, namely the atom 3 of the piperidinedione cycle. If the substituents R 1 and R 2 , on the one hand, or R 3 and R 4 , on the other hand, are different from each other, there are one or two other asymmetric carbon atoms in the molecule. As a result, the compounds (I) can exist in the form of diastereoisomers and optical isomers. All these isomers and their mixtures are an integral part of the invention.
  • the compounds according to the invention are obtained from a pyridylacetonitrile according to one of the preparation methods indicated below:
  • Pyridylacetonitrile 1 is first of all subjected to an alkylation reaction with a compound: (Hal representing a halogen) in the presence of an organic or mineral base to yield compound 2.
  • reaction can also be carried out in the presence of sodium amide in the liquid ammonia at a temperature between -30 and -40 ° C.
  • Either hydrochloric acid is used in acetic acid medium, or concentrated sulfuric acid or polyphosphoric acid at a temperature between 100 and 150 ° C.
  • the operation is carried out in an inert solvent, such as benzene, most often at the boiling point of the solvent, adding as catalyst either paratoluenesulfonic acid or piperidine and acetic acid.
  • Derivative 4 is transformed into the corresponding saturated derivative by catalytic reduction.
  • the operation is carried out in solution in ethanol in the presence of a hydrogenation catalyst such as palladium on carbon at ambient temperature under atmospheric pressure.
  • Compound 5 is substituted on the carbon at ⁇ of the nitrile by the action of a compound: in the presence of a sodating agent, such as sodium hydride, in a solvent such as dimethylformamide. Most often, one operates at a temperature between 20 and 50 ° C.
  • a sodating agent such as sodium hydride
  • Dinitrile 9 is then replaced by the action of a halogenated derivative to obtain dinitrile 10.
  • the operation is carried out in the presence of a sodating agent such as sodium hydride in an inert solvent such as dimethylformamide.
  • the dinitrile 10 is cyclized by the action of a concentrated mineral acid such as sulfuric acid, at a temperature between 80 and 120 ° C.
  • a concentrated mineral acid such as sulfuric acid
  • the nitrile 8 is substituted with 1-chloro-2-bromoethane to obtain the chlorinated nitrile 11.
  • the substitution is preferably carried out in the presence of lithium diethylamide (prepared in situ by the action of diethylamine on butyllithium) at room temperature , in an inert solvent such as ether or tetrahydrofuran.
  • dinitrile 12 By acting on 11 of a cyanide and preferably tetraethylammonium cyanide, dinitrile 12 is obtained.
  • the operation is carried out in a solvent for the two reactants such as acetonitrile at a temperature of 40 to 60 ° C.
  • Dinitrile 12 is replaced by bromopyridine to obtain dinitrile 13.
  • the operation is carried out in the presence of lithium diisopropylamide in a solvent such as tetrahydrofuran and at a temperature of -10 to -20 ° C.
  • Dinitrile 13 is replaced a second time by a halogenated derivative operating in an identical manner to that used for dinitrile 10 in method C.
  • the salts of the compounds (I) are obtained by the usual methods of salification.
  • the mixture is heated at 35 ° C for 5 h. After cooling, water is added and extracted with ether. The organic phase is separated, dried over sodium sulfate and then the solvent is evaporated to dryness.
  • the solvent is evaporated to dryness and the residue is taken up in water and ether.
  • the ethereal phase is separated and the aqueous phase is re-extracted with ether.
  • the ethereal extracts are combined, washed with water and dried over sodium sulfate.
  • the solvent is evaporated to dryness.
  • Example 1b The procedure is as in Example 1b), starting from the nitrile of Example 1a), but replacing methacrylonitrile with acrylonitrile.
  • Example 1b The procedure is as in Example 1b), starting from the nitrile of Example 1a), but replacing the methacrylonitrile with an equivalent amount of 2-isopropyl acrylonitrile
  • the pure diastereomer is recrystallized from isopropyl ether; Mp 123-125 ° C.
  • the crude reaction product is chromatographed on an alumina column (25 g of alumina per gram of the product), eluting with an ethyl acetate-pentane mixture, 15-85 vol / vol.
  • the first diastereoisomer is first obtained: tertiobutyl-5 (e) (2-diisopropylamino ethyl) -3 (e) (pyridyl-2) -3 (a) piperidinedione-2,6 (SR 41494); weight: 8.7 g, mp 101-102 ° C (hexane).
  • the ethereal phase is separated and the aqueous phase is re-extracted with ether.
  • the ethereal extracts are combined and dried over sodium sulfate.
  • the solvent is evaporated to dryness and the residue is chromatographed on an alumina column with the eluent mixture ethyl acetate-pentane 2.5-100 vol / vol.
  • the unreacted products are removed at the head, then 12.5 g of the expected product are obtained, used as it is for cyclization.
  • Cyclization is carried out with sulfuric acid as indicated in Example 3b).
  • the expected product is obtained in the form of colorless crystals, mp 105-106 ° C (cyclohexane-hexane).
  • the mixture is brought to reflux until no more water separates (approximately 69 h) then, after cooling, the organic solution is washed with a sodium bicarbonate solution. The solution is dried over sodium sulfate, then the solvent is evaporated to dryness.
  • the product is used as is for the next step.
  • the product obtained above is dissolved in 600 ml of ethanol and 15 g of 5% palladium on carbon are added. Hydrogenation is carried out at ambient temperature under 1 atmosphere. The catalyst is filtered and the solvent is evaporated to dryness.
  • the solvent is evaporated to dryness and the residue is taken up in ether.
  • the solution is washed with water, dried over sodium sulfate and the solvent is evaporated to dryness.
  • step a By operating in the same way, but by replacing, in step a), methyl-3 (2-pyridyl) -2 butene-2 nitrile by an equivalent amount of (2-pyridyl) -2-butene-2 nitrile, in the same way, (diisopropylamino-2 ethyl) -3 (pyridyl-2) -3 trimethyl-4,5,5-piperidinedione-2,6 is obtained; colorless crystals; Mp 93-94 ° C (isopropyl ether) (SR 42480).
  • the products of the invention have been studied in pharmacology, in particular with a view to demonstrating their antiarrhythmic properties.
  • the antiarrhythmic power of these molecules was assessed on an animal model of ventricular arrhythmia.
  • Bastard dogs are anesthetized and then subjected to the placement, by retrograde catheterization, of a metal coil in the coronary bed.
  • a frequency modulator micro-transmitter is attached to the back of the animal and connected to two precordial electrodes.
  • the animal returned to its box then shows a progressive thrombosis of the anterior interventricular artery.
  • a localized and transmural myocardial infarction is created, generating an abnormal but repetitive electrical activity: ventricular tachycardia.
  • the drugs are administered per os and the telemetric system makes it possible to follow in real time the evolution of the dog's arrhythmia.
  • a count of the sinus and pathological systolic complexes is continuously ensured by electronic methods. Thus, we can quantify the quality and duration of action of the product and observe the behavior of the animal.
  • a product is considered active when it removes at least 60% of the abnormal complexes or when it restores the sinus rhythm.
  • the products (I) are not very toxic and especially no sign of toxicity could be demonstrated at the doses where they are active on dysrhythmias.
  • the products (I) can be used in human therapy as myocardial protectors for the correction of ventricular rhythm disorders of ischemic origin.
  • the products may be presented in dosage forms corresponding to the oral route (tablets, capsules, etc.) and the parenteral route (injectable ampoules).
  • the dose required to restore the sinus rhythm in humans is between 50 and 150 mg intravenously and between 400 and 800 mg orally, per day, approximately.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (10)

1. Piperidindionderivate der allgemeinen Formel I
Figure imgb0085
worin
R für eine gerade oder verzweigte Alkylgruppe mit 2 bis 5 Kohlenstoffatomen steht, oder aber
- die Gruppe
Figure imgb0086
 eine gegebenenfalls durch 1 bis 4 Methylgruppen substituierte Morpholino. oder Piperidinogruppe darstellt,
n = 2 oder 3,
R1' R2, R3 und R4, unabhängig voneinander, ein Wasserstoffatom oder eine gerade oder verzweigte Alkylgruppe mit 1 bis 4 Kohlenstoffatomen darstellen, oder
R3 und R4, zusammen genommen, eine Gruppe (CH2)m bedeuten, worin m = 4 oder 5, oder aber R2 und R3, zusammen genommen, eine Gruppe (CH2)p darstellen, worin p = 3 oder 4, und in diesem Fall R1 und R4 Wasserstoff sind,
R5 Wasserstoff oder eine gerade oder verzweigte Alkylgruppe mit 1 bis 4 Kohlenstoffatomen bezeichnet,
- und schließlich das Piperidindion die Pyridylgruppe in 2', 3' oder 4' substituiert, sowie die Salze der Derivate mit pharmazeutisch akzeptablen Säuren.
2. Derivate nach Anspruch 1 in Form eines Diastereoisomeren oder optischen Isomeren oder einer Mischung dieser lsomeren.
3. Verfahren zur Herstellung von Piperidindionderivaten nach Anspruch 1 der Formel I, worin R4 = R5 = H, dadurch gekennzeichnet, daß
- in einer ersten Stufe die Alkylierung von Pyridylacetonitril mit einer Verbindung der Formel
Figure imgb0087
worin Hal für ein Halogen steht, durchgeführt wird, wobei die Reaktion in Gegenwart einer Base erfolgt,
- dann auf das erhaltene Produkt ein a-ungesättigtes Nitril der Formel
Figure imgb0088
einwirken gelassen wird, wobei die Reaktion in Gegenwart eines quaternären Ammoniumhydroxids ausgeführt wird,
- die so erhaltene Verbindung danach durch Erhitzen in saurem Milieu zyklisiert wird,
- und gegebenenfalls durch Einwirken einer pharmazeutisch akzeptablen Mineral- oder organischen Säure in eines ihrer Salze übergeführt wird.
4. Verfahren zur Herstellung von Piperidindionderivaten nach Anspruch 1 der Formel I, worin R1 = R2 = R5 = H, dadurch gekennzeichnet, daß :
- in einer ersten Stufe ein Carbonylderivat der Formel
Figure imgb0089
mit Pyridylacetonitril zur Umsetzung gebracht wird,
- dann das so erhaltene Produkt katalytisch reduziert wird, sodaß das ungesättigte Derivat in ein gesättigtes Derivat übergeführt wird,
- dann auf das gesättigte Derivat ein a-Nitril der Formel
Figure imgb0090
einwirken gelassen wird,
- das so erhaltene Derivat danach durch Erhitzen in saurem Milieu zyklisiert wird,
- und gegebenenfalls durch Einwirken einer pharmazeutisch akzeptablen Mineral- oder organischen Säure in eines seiner Salze übergeführt wird.
5. Verfahren zur Herstellung von Piperidindionderivaten nach Anspruch 1 der Formel I, worin R5 = H. dadurch gekennzeichnet, daß
- in einer ersten Stufe die Umsetzung eines ungesättigten Nitrils der Formel
Figure imgb0091
mit einem Nitril der Formel
Figure imgb0092
durchgeführt wird, wobei die Reaktion in Gegenwart eines Metall-Diisopropylamids bei niedriger Temperatur und in Lösung in einem Lösungsmittel erfolgt,
- dann das so erhaltene Produkt mit einem halogenierten Derivat der Formel
Figure imgb0093
zur Umsetzung gebracht wird, wobei diese Reaktion in Gegenwart eines natrisiernden Mittels in einem inerten Lösungsmittel durchgeführt wird,
- das so erhaltene Produkt danach durch Erhitzen in saurem Milieu zyklisiert wird,
- und gegebenenfalls durch Einwirken einer pharmazeutisch akzeptablen Mineral- oder organischen Säure in eines seiner Salze übergeführt wird.
6. Verfahren zur Herstellung von Piperidindionderivaten nach Anspruch 1 der Formel I, worin R1 = R2 = R5 = H, dadurch gekennzeichnet, daß
- in einer ersten Stufe das Nitril der Formel
Figure imgb0094
mit 1-Chlor-2-brom-äthan zur Umsetzung gebracht wird, wobei die Reaktion in Gegenwart von Lithiumdiäthylamid bei Umgebungstemperatur in einem inerten Lösungsmittel durchgeführt wird,
- und dann das so erhaltene Produkt mit Tetraäthylammoniumcyanid bei einer Temperatur von 40 .bis 60 °C in einem Lösungsmittel reagieren gelassen wird,
- das so erhaltene Dinitril danach mit Brompyridin in Gegenwart von Lithiumdiisopropylamid in einem inerten Lösungsmittel und bei einer Temperatur zwischen -10 und -20°C zur Umsetzung gebracht wird,
- danach das so erhaltene Produkt mit einem halogenierten Derivat der Formel
Figure imgb0095
reagieren gelassen wird, wobei die Reaktion in Gegenwart eines natrisierenden Mittels in einem inerten Lösungsmittel durchgeführt wird,
- das so erhaltene Produkt danach durch Erhitzen in saurem Milieu zyklisiert wird,
- und gegebenenfalls durch Einwirken einer pharmazeutisch akzeptablen Mineral- oder organischen Säure in eines seiner Salze übergeführt wird.
7. Verfahren nach einem der Ansprüche 3 bis 6, dadurch gekennzeichnet, daß die so erhaltene Verbindung der Formel I, worin R5 für H steht, vor einer möglichen Salzbildung durch Alkylieren am Stickstoff nach bekannten Alkylierungsverfahren in eine Verbindung der Formel I, worin R5 eine gerade oder verzweigte Alkylgruppe mit 1 bis 4 Kohlenstoffatomen darstellt, übergeführt wird.
8. Verfahren nach einem der Ansprüche 3 bis 7, dadurch gekennzeichnet, daß die so erhaltene Verbindung der Formel I in Form eines Diastereoisomeren, eines optischen Isomeren oder einer Mischung dieser Isomeren isoliert wird.
9. Medikamente, dadurch gekennzeichnet, daß sie mindestens ein Piperidindionderivat nach einem der Ansprüche 1 oder 2 enthalten.
10. Medikamente zum Myokardschutz, dadurch gekennzeichnet, daß sie zwischen 50 und 800 mg mindestens eines Piperidindionderivats nach einem der Ansprüche 1 oder 2 enthalten.
EP83402142A 1982-11-08 1983-11-04 Piperidindion-Derivate mit herzmuskelschonender und antiarrhythmischer Wirkung, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel Expired EP0110755B1 (de)

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Application Number Priority Date Filing Date Title
AT83402142T ATE22561T1 (de) 1982-11-08 1983-11-04 Piperidindion-derivate mit herzmuskelschonender und antiarrhythmischer wirkung, verfahren zu ihrer herstellung und sie enthaltende arzneimittel.

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FR8218706A FR2535721A1 (fr) 1982-11-08 1982-11-08 Derives de la piperidinedione protecteurs du myocarde presentant une acticite antiarythmique, leur procede de preparation et les medicaments qui contiennent lesdits derives
FR8218706 1982-11-08

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AT (1) ATE22561T1 (de)
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HU (1) HU191494B (de)
IE (1) IE56209B1 (de)
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PL (3) PL140021B1 (de)
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US4668689A (en) * 1984-07-19 1987-05-26 National Research Development Corporation Glutarimide derivatives for treating oestrogen-dependent tumors
US5238947A (en) * 1990-04-12 1993-08-24 University Of Georgia Research Foundation, Inc. Synthetic piperidinediones with cytostatic activity
JP6068451B2 (ja) 2011-05-17 2017-01-25 ザ・リージエンツ・オブ・ザ・ユニバーシテイ・オブ・カリフオルニア キナーゼ阻害剤
US9376438B2 (en) 2011-05-17 2016-06-28 Principia Biopharma, Inc. Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors
JP5974084B2 (ja) 2011-05-17 2016-08-23 プリンシピア バイオファーマ インコーポレイテッド チロシンキナーゼ阻害剤
NZ630925A (en) 2012-09-10 2016-10-28 Principia Biopharma Inc Pyrazolopyrimidine compounds as kinase inhibitors
US8957080B2 (en) 2013-04-09 2015-02-17 Principia Biopharma Inc. Tyrosine kinase inhibitors
ES2841248T3 (es) 2014-02-21 2021-07-07 Principia Biopharma Inc Sales y forma sólida de un inhibidor de BTK
US10485797B2 (en) 2014-12-18 2019-11-26 Principia Biopharma Inc. Treatment of pemphigus
US20180305350A1 (en) 2015-06-24 2018-10-25 Principia Biopharma Inc. Tyrosine kinase inhibitors
CN115054586B (zh) 2016-06-29 2024-08-02 普林斯匹亚生物制药公司 改性的释放制剂

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US2664424A (en) * 1953-12-29 Dioxo-piperidines
GB1455687A (en) * 1972-12-28 1976-11-17 Aspro Nicholas Ltd Pharmacologically active 3-phenyl-3-aminoalkyl-2,6-dioxo-hydro genated pyridines
FR2467200A1 (fr) * 1979-10-11 1981-04-17 Clin Midy Derives du pyrrole actifs sur les troubles du rythme cardiovasculaire

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PT77607A (fr) 1983-12-01
FI834087A (fi) 1984-05-09
IE56209B1 (en) 1991-05-22
DD229407A5 (de) 1985-11-06
NO159852B (no) 1988-11-07
CS244681B2 (en) 1986-08-14
NO834057L (no) 1984-05-09
ES527091A0 (es) 1984-07-01
YU184285A (en) 1986-06-30
IL70099A0 (en) 1984-01-31
YU184185A (en) 1986-06-30
FR2535721A1 (fr) 1984-05-11
GR78747B (de) 1984-10-02
NO159852C (no) 1989-02-15
HU191494B (en) 1987-02-27
DK511383D0 (da) 1983-11-08
PL140021B1 (en) 1987-03-31
FI834087A0 (fi) 1983-11-08
KR900006721B1 (ko) 1990-09-20
AU565519B2 (en) 1987-09-17
SU1333237A3 (ru) 1987-08-23
IL70099A (en) 1987-10-20
DE3366623D1 (en) 1986-11-06
ZA838065B (en) 1984-06-27
PL139946B1 (en) 1987-03-31
US4721710A (en) 1988-01-26
FI79536B (fi) 1989-09-29
KR840006641A (ko) 1984-12-01
PT77607B (fr) 1986-03-18
DD219770A5 (de) 1985-03-13
MA19948A1 (fr) 1984-07-01
PL244462A1 (en) 1985-02-13
FR2535721B1 (de) 1985-05-17
PL249749A1 (en) 1985-03-12
ATE22561T1 (de) 1986-10-15
JPS59161377A (ja) 1984-09-12
OA07582A (fr) 1985-03-31
YU221183A (en) 1986-06-30
ES8406070A1 (es) 1984-07-01
NZ206177A (en) 1985-11-08
CA1221967A (en) 1987-05-19
FI79536C (fi) 1990-01-10
SU1316558A3 (ru) 1987-06-07
PH20421A (en) 1987-01-05
EP0110755A1 (de) 1984-06-13
PL249750A1 (en) 1985-03-12
DD229402A5 (de) 1985-11-06
SU1333238A3 (ru) 1987-08-23
PL140992B1 (en) 1987-06-30
AU2089883A (en) 1984-05-17
IE832581L (en) 1984-05-08
SG1989G (en) 1989-06-02
DK511383A (da) 1984-05-09

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